Process for the preparation of heteroaryl-phenylalanines

ABSTRACT

A process for the preparation of heteroaryl-phenylalanines of formula (II) in which R is a hydrogen atom, a straight or branched C1 -C4 alkyl groups or a benzyl group; R1 is an optionally substituted 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur; comprising a cross-coupling reaction among heteroaryl-zinc halide and phenylalanine derivatives is described. Compounds of formula (II) are intermediates useful for the preparation of compounds endowed with pharmacological activity.

[0001] The present invention relates to a process for the preparation ofheteroaryl-phenylalanines and, more particularly, it relates to across-coupling process for the preparation of phenylalanine derivativeshaving the phenyl group substituted by a heteroaryl group.

[0002] Heteroaryl-phenylalanines are known compounds, well described inthe literature. For example, heteroaryl-phenylalanines endowed withpharmacological activity as antihypertensive agents have been describedin the British patent n° 1554667 (Merck & Co., Inc.).

[0003] Moreover, heteroaryl-phenylalanines can be used as syntheticintermediates for the preparation of compounds endowed withpharmacological activity.

[0004] In the International patent application no. WO 97/24342 in thename of the same applicant, heteroaryl-phenylalanines are used for thepreparation of N-mercaptoacyl derivatives of phenylalanine of formula

[0005] wherein

[0006] R is a hydrogen atom, a straight or branched C₁-C₄ alkyl group ora benzyl group;

[0007] R₁ is a 5 or 6 membered aromatic heterocyclic group, optionallysubstituted, having 1 or 2 heteroatoms selected among nitrogen oxygenand sulphur;

[0008] R₂ is a C₂-C₄ straight or branched alkyl group or an aryl orarylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety inwhich the aryl group is phenyl or a 5 or 6 membered aromaticheterocyclic group having 1 or 2 heteroatoms selected among nitrogen,oxygen and sulphur, optionally substituted by one or more substituents,the same or different, selected among halogen atoms, hydroxy groups,alkoxy, alkyl, alkylthio, alkylsulfonyl or alkoxycarbonyl groups havingfrom 1 to 6 carbon atoms in the alkyl moiety, C₁-C₃ alkyl groupscomprising one or more fluorine atoms, carboxy groups, nitro groups,amino or aminocarbonyl groups, acylamino groups, aminosulfonyl groups,mono- or di-alkylamino or mono- or di-alkylaminocarbonyl groups havingfrom 1 to 6 carbon atoms in the alkyl moiety;

[0009] R₃ is a mercapto group or a R₄COS group convertible into amercapto group in the body in which R₄ is a straight or branched C₁-C₄alkyl group or a phenyl group.

[0010] Such compounds are endowed with metallopeptidases inhibitoryactivity and are useful in therapy for the treatment of cardiovasculardiseases.

[0011] Many processes for the preparation of heteroaryl-phenylalaninesare described in the literature.

[0012] Within this field, the processes comprising cross-couplingreactions starting from heterocyclic compounds and phenylalaninederivatives are particularly attractive.

[0013] For example, 4-(2-furanyl)-phenylalanine is prepared following across-coupling process comprising the reaction betweenN-(tert-butoxycarbonyl)-tyrosine triflate methyl ester and2-furanboronic acid in the presence ofpalladium(0)tetrakis(triphenylphosphine) as described by W. C. Shieh inJ Org Chem. 1992, 57, 379-381.

[0014] Nevertheless, as reported by the same Author, for the preparationof such a compound with valuable yield, amounts of catalyst equal to 30%in moles compared to 2-furanboronic acid, significantly higher than theones requested for the conversion of other arylboronics substrates, i.e.phenylboronics, are needed.

[0015] An alternative route to the above process for the preparation ofthienyl-phenylalanine, essentially comprising a cross-coupling reactionbetween thienylboronic acids and bromo-phenylalanine in the presence ofpalladium acetate and tri(o-tolyl)phosphine, has been described by M. J.Burk et al. in J. Am. Chem. Soc. 1994, 116, 10847-10848.

[0016] The arylboronic derivatives used as synthetic intermediates inthe above processes are in turn prepared from the correspondingaryl-magnesium or aryl-lithium derivatives, by reaction withtrialkylborates.

[0017] Nevertheless, to avoid the formation of di- or tri-arylboronderivatives as by-products, the preparation of the arylboronic acids,for example 2- and 3-furanboronic acids, requires reaction temperaturesparticularly low equal to −70° C. (J. Org. Chem. 1984, 49, 5237-5243).

[0018] According to an alternative synthetic process, theheteroaryl-phenylalanines can be prepared by cross-coupling betweenhalogenated heterocyclic derivatives and stannyl-phenylalaninederivatives (Bioconjugate Chem., 1993, 4, 574-580); nevertheless thealkyistannanes used for the preparation of stannyl-phenylalanines arehighly toxic compounds.

[0019] Therefore, the high toxicity and the prolonged and difficultpreparation of some intermediates make the cross-coupling processes forthe synthesis of heteroaryl-phenylalanine, described in the literature,unsuitable for industrial application

[0020] Now we have found a process for the preparation ofheteroaryl-phenylalanines by cross-coupling reaction that usesorgano-zinc compounds, easily practicable and particularly indicated foran industrial application.

[0021] Therefore, object of the present invention is a process for thepreparation of heteroaryl-phenylalanines of formula

[0022] in which

[0023] R is a hydrogen atom, a straight or branched C₁-C₄ alkyl groupsor a benzyl group;

[0024] R₁ is an optionally substituted 5 or 6 membered aromaticheterocyclic group with one or two heteroatoms selected among nitrogen,oxygen and sulphur;

[0025] that comprises the reaction between a compound of formula

R₁—Zn—Y  (III)

[0026] in which

[0027] R₁ has the above reported meanings and Y is a chlorine, bromineor iodine atom; and a compound of formula

[0028] in which

[0029] R has the above reported meanings;

[0030] R′ is an optionally protected amino group,

[0031] X is an iodine or bromine atom or a methansulfonyloxy,fluoromethansulfonyloxy, p toluensulfonyloxy ortrifluoromethansulfonyloxy group;

[0032] in the presence of a transition-metal (0) based catalyst;

[0033] and, when R′ is a protected amino group, the deprotectionreaction of the amino group.

[0034] The process object of the present invention is easily practicableand it enables to obtain the heteroaryl-phenylalanines of formula IIwith high yields, equal to or greater than 80% with respect to thestarting compound of formula IV.

[0035] The cross-coupling reaction, according to the process object ofthe present invention, is carried out by reaction between an organo-zinccompound of formula III and a compound of formula IV.

[0036] Preferably, compound III and compound IV are used in a molarratio III:IV from 1:1 to 3:1.

[0037] Still more preferably, the molar ratio of the compounds III:IV isfrom 1:1 to 2:1.

[0038] In the process object of the present invention the compounds offormula IV in which X is a iodine atom are preferably used.

[0039] The cross-coupling reaction is carried out in the presence of atransition-metal(0) based catalyst.

[0040] The amount of the catalyst is preferably from 0.05% to 5% inmoles with respect to the organo-zinc compound of formula III.

[0041] Preferred examples of transition-metal(0) based catalysts areoptionally supported palladium or nickel, in the presence of ligandssuch as, for example, triphenylphosphine.

[0042] The transition-metal(0) based catalysts can be optionallyprepared in situ starting from the corresponding salts such as, forexample, nickel chloride, cobalt chloride, nickel acetylacetonate,ferric chloride, palladium chloride, lithium tetrachlorocuprate,palladium acetate and palladium acetylacetonate.

[0043] Exclusively for practical reasons, palladiumtetrakis(triphenylphosphine), nickel tetrakis(triphenylphosphine) orpalladium on charcoal in the presence of triphenylphosphine, optionallyprepared in situ as described, for example, in Org Synth., 66, 67-74,1988, are preferred.

[0044] The cross-coupling reaction is carried out in the presence of anorganic solvent.

[0045] Suitable organic solvents are, for example, C₆-C₁₂ aliphatichydrocarbons, tetrahydrofuran, di-ethyl ether, methyl-lert-butyl ether,ethylene glycol di-methyl ether, dioxane, toluene, xylene or mixturesthereof.

[0046] Preferably tetrahydrofuran, toluene or mixtures thereof are used.

[0047] Usually the reaction temperature is between 20° C. and the refluxtemperature of the reaction mixture.

[0048] Preferably, a temperature between 40° C. and 60° C. is used.

[0049] From a practical point of view, the use of a compound of formulaIV in which R′ is a protected amino group is preferred for thepreparation of the compounds of formula II.

[0050] Examples of suitable protecting groups are acetyl,benzyloxycarbonyl, tert-butoxycarbonyl, formyl, benzyl, ethoxycarbonyland phthaloyl.

[0051] Preferably, the protective group is tert-butoxycarbonyl orformyl.

[0052] The starting compounds of formula IV in which R′ is a protectedamino group are known compounds or they are easily prepared according toknown methods from the corresponding derivatives of formula IV in whichR′ is an amino group (H₂N—) (Bioconjugate Chem. 1993, 4, 574-580).

[0053] When R′ is a protected amino group, the compounds of formula IIaccording to the present process are prepared by cross-coupling reactionand subsequent deprotection of the amino group.

[0054] The deprotection is carried out according to standard procedures.

[0055] For a general reference on the use of protective groups inorganic chemistry see Theodora W. Greene and Peter G. M. Wuts“Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc., IIEd., 1991.

[0056] Usually, the cross-coupling reaction is carried out starting froma compound of formula IV in which R is different from hydrogen, henceobtaining the corresponding compounds of formula II (R different fromhydrogen). From these, by working according to conventional procedures,the corresponding compounds of formula II in which R═H can be obtained.

[0057] The starting compounds of formula III are known compounds or theyare easily prepared according to known methods.

[0058] For example, the compounds of formula III can be prepared byreaction of the corresponding heteroaryl-lithium or heteroaryl-magnesiumderivatives with an anhydrous zinc halide, e.g. zinc chloride, aslikewise reported in Heterocycles, Vol. 31, No 12, 1990, 2181-2186.Examples of compounds of formula II, that can be prepared according tothe process object of the present invention, are the compounds in whichthe R₁ group is an aromatic heterocyclic group such as, for example,thiazole, isoxazole, oxazole, isothiazole, pyrazole, imidazole,thiophene, pyrrole, pyridine, pyrimidine, pyrazine, pyridazine andfuran.

[0059] Specific examples of compounds of formula II are:

[0060] 4-(2-thiazolyl)-phenylalanine;

[0061] 4-(2-pyridyl)-phenylalanine;

[0062] 4-(3-pyridyl)-phenylalanine;

[0063] 4-(2-furyl)-phenylalanine;

[0064] 4-(3-furyl)-phenylalanine;

[0065] 4-(5-pyrimidinyl)-phenylalanine;

[0066] 4-(2-pyrazinyl)-phenylalanine;

[0067] 4-(2-thienyl)-phenylalanine;

[0068] 4-(3 -thienyl)-phenylalanine;

[0069] and the corresponding methyl and ethyl esters.

[0070] According to a particularly advantageous aspect of the processobject of the present invention, the starting compounds of formula IIIare prepared in situ from the corresponding heteroaryl-lithium orheteroaryl-magnesium derivatives and hence directly used in thecross-coupling reaction.

[0071] More particularly, the heteroaryl-lithium or heteroaryl-magnesiumderivatives are reacted with an anhydrous zinc halide, in the presenceof the same solvent used for the cross-coupling reaction, to obtain thecorresponding heteroaryl-zinc derivatives of formula III.

[0072] Therefore, the in situ so prepared compounds of formula III arereacted with the compounds of formula IV, according to the processobject of the present invention.

[0073] The preparation of compounds of formula III is carried out usinga molar ratio anhydrous zinc halide: heteroaryl-lithium orheteroaryl-magnesium derivative from 1:1 to 3:1.

[0074] Preferably, the heteroaryl-zinc derivatives of formula III areprepared with anhydrous zinc chloride.

[0075] The heteroaryl-lithium or heteroaryl-magnesium derivatives areknown compounds or they are easily prepared according to known methods,as described, for example. in J. Am. Chem. Soc. 1952, 74, 6260-6262 orin the just mentioned Heterocycles, Vol. 31, No. 12, 1990, 2181-2186.

[0076] In a preferred embodiment of the process object of the presentinvention, the compounds of formula II are prepared starting from thecorresponding heteroaryl-magnesium derivatives, by their reaction withan anhydrous zinc halide and subsequent cross-coupling reaction of theresultant compounds of formula III, in the same medium, as previouslydescribed.

[0077] The compounds of formula II can be used as syntheticintermediates for the preparation of compounds endowed withpharmacological activity such as, for example, the N-mercaptoacylderivatives of phenylalanine of formula I, as disclosed in the justmentioned International patent application no. WO 97/24342.

[0078] In a particularly preferred embodiment, the process object of thepresent invention is used for the preparation of the compounds endowedwith pharmacological action described in the aforesaid Internationalpatent application.

[0079] In a preferred embodiment of the process object of the presentinvention, a suitable amount of heteroaryl-magnesium halide is treatedwith an anhydrous zinc halide in a molar ratio respectively equal to1:2, at room temperature and in the presence of a suitable solvent.

[0080] Therefore the compound of formula IV, properly protected, isadded to the reaction mixture containing the in situ so preparedcompound of formula III.

[0081] The cross-coupling reaction is carried out in the presence ofcatalytic amounts, for example equal to 1% in moles, of an in situprepared palladium based catalyst.

[0082] The compounds of formula II, in the protected form, are thusobtained, in high yields, by heating the reaction mixture.

[0083] The subsequent deprotection reaction, carried out according tostandard procedures, leads to the compounds of formula II.

[0084] The resultant compounds of formula II can be used as such, forexample as synthetic intermediates for the preparation ofpharmacologically active compounds.

[0085] The process object of the present invention is easily practicableand it enables to obtain the heteroaryl-phenylalanines of formula IIwith high yields and with mild reaction conditions.

[0086] Moreover, starting from a compound of formula IV as a singlestereoisomer, the process object of thre present invention enables toobtain the compounds of formula II with a high optical purity, withoutany racemization.

[0087] Finally, the use of particularly stable intermediates, easilyobtainable and usable in situ for the subsequent reactions without anyfurther purification step, makes the process object of the presentinvention particularly suitable for the industrial application. With theaim to illustrate the present invention the following examples are nowgiven.

EXAMPLE 1

[0088] Preparation ofN-(tert-butoxycarbonyl)4-(2-thiazolyl)-L-phenylalanine methyl ester

[0089] A solution of 2-thiazolyl magnesium bromide, prepared startingfrom 2-bromo-thiazole (0.528 Kg; 3.22 moles) and magnesium turnings(0.093 Kg; 3.82 moles) in a 1:1 mixture of tetrahydrofuran:toluene (1.8l), was slowly added in 2 hours to a suspension, prepared by slow addinganhydrous zinc chloride (0.853 Kg; 6,27 moles) in tetrahydrofuran (1.92l ), under stirring and in an inert atmosphere at the temperature of 30°C.

[0090] The mixture was heated at 50° C. andN-(tert-butoxycarbonyl)-4-iodo-L-phenylalanine methyl ester (1.0 Kg;2.34 moles) was gradually added.

[0091] A previously prepared mixture of palladium acetate (8 g, 0.036moles) and triphenylphosphine (19.2 g; 0.072 moles) was added to theresultant mixture.

[0092] The mixture, kept under stirring at the temperature of 50° C. for2 hours up to completion of the reaction (TLC hexane: ethylacetate=7:3), was then cooled at room temperature and poured into an iceand water (3 Kg) bath containing toluene (1 l)

[0093] At that time glacial acetic acid (130 g) was added and the phaseswere separated. The aqueous phase was extracted with toluene (0.5 l) andthe combined organic phases were washed twice with water (2.2 l) andevaporated to dryness under vacuum affordingN-(tert-butoxycarbonyl)-4-(2-thiazolyl)-L-phenylalanine methyl ester(1.19 Kg), used as such in the subsequent reaction.

EXAMPLE 2

[0094] Preparation ofN-(tert-butoxycarbonyl)-4-(2-thiazolyl)-D,L-phenylalanine methyl ester

[0095] A solution of 2-thiazolyl magnesium bromide prepared by2-bromo-thiazole (1.8 g; 11 mmoles) and magnesium turnings (320 mg; 13.1mmoles) in a 1:1 mixture of tetrahydrofuran:toluene (6.6 ml) wasgradually added in 0.5 hours to a suspension, prepared by graduallyadding anhydrous zinc chloride (3 g; 22 mmoles) to tetrahydrofuran (6.6ml), kept under stirring and under inert atmosphere at 30° C.

[0096] Then, the mixture was heated to 50° C. andN-tert-butoxycarbonyl)-4-bromo-D,L-phenylalanine methyl ester (1.6 g;4.5 mmoles) was added.

[0097] Palladium acetate (33.6 mg; 0.15 mmoles) and triphenylphosphine(118 mg, 0.45 mmoles) were added to the resultant mixture.

[0098] The mixture, kept under stirring at 50° C. for 15 hours, was thencooled up to room temperature and poured into an ice and water bath (10ml) containing toluene (10 ml).

[0099] Then, glacial acetic acid (about 1 g) was added and the phaseswere separated The organic phase was evaporated to dryness.

[0100] The residue consisted of about 70% ofN-(tert-butoxycarbonyl)-4-(2-thiazolyl)-D,L-phenylalanine methyl esterand of about 15% of starting compound (TLC eluenthexane:ethylacetate=6:4).

EXAMPLE 3

[0101] Preparation of N-formyl-4-(2-thiazolyl)-L-phenylalanine methylester

[0102] By working in a way similar to that described in example 1 butstarting from N-formyl-4-iodo-L-phenylalanine methyl ester,N-formyl-4-(2-thiazolyl)-L-phenylalanine methyl ester was obtained(yield>90%) as a crude to be used as such without any furtherpurification.

EXAMPLE 4

[0103] Preparation of 4-(2-thiazolyl)-L-phenylalanine methyl esterdihydrochloride

[0104] Thionyl chloride (0.48 Kg; 4.03 moles) was added dropwise, in 1.5hours, to a solution ofN-(tert-butoxycarbonyl)-4-(2-thiazolyl)-L-phenylalanine methyl ester(1.208 Kg; 2.06 moles), prepared as described in example 1, in methanol(1.6 l), kept under stirring, under inert atmosphere and at atemperature of 15° C.

[0105] At the end of the addition, the suspension was allowed to warm to25° C. and kept under stirring for 1 hour.

[0106] Methylethylketone (3.4 l) was then added to the resultant mixtureand, by heating to reflux, the mixture of solvents (1.9 l) wasdistilled.

[0107] The resultant suspension was cooled to 20° C. and the formedprecipitate was filtered and washed with methylethylketone (3×0.3 l)yielding, after drying under vacuum, 4-(2-thiazolyl)-L-phenylalaninemethyl ester dihydrochloride [820 g; 91.5% yield calculated onN-(tert-butoxycarbonyl)-4-iodo-L-phenylalanine methyl ester described inexample 1; HPLC titre 87%].

1. A process for the preparation of heteroaryl-phenylalanines of formula

in which R is a hydrogen atom, a C₁-C₄ straight or branched alkyl groupor a benzyl group; R₁ is an optionally substituted 5 or 6 memberedaromatic heterocyclic group with one or two heteroatoms selected amongnitrogen, oxygen or sulphur; that comprises the reaction between acompound of formula R₁—Zn—Y  (iii) in which R₁ has the above reportedmeanings and Y is a chlorine, bromine or iodine atom, and a compound offormula

in which R has the above reported meanings; R′ is an optionallyprotected amino group, X is an iodine or bromine atom or amethansulfonyloxy, fluoromethansulfonyloxy, p,toluensulfonyloxy, ortrifluoromethansulfonyloxy group; in the presence of a transition-metal(0) based catalyst; and, when R′ is a protected amino group, thedeprotection reaction of the amino group.
 2. A process according toclaim 1 in which the compounds III and IV are used in a molar ratio from1:1 to 3:1.
 3. A process according to claim 2 in which the molar ratiois from 1:1 to 2:1.
 4. A process according to claim 1 in which thecompound of formula IV wherein X is an iodine atom is used.
 5. A processaccording to claim 1 in which the amount of catalyst is from 0 05% to 5%in moles with respect to the organo-zinc compound of formula III.
 6. Aprocess according to claim 1 wherein the catalyst is an optionallysupported palladium or nickel-based catalyst, in the presence ofligands.
 7. A process according to claim 6 in which the catalyst isselected among palladium tetrakis(triphenylphosphine), nickeltetrakis(triphenylphosphine) or palladium on charcoal in the presence oftriphenylphosphine.
 8. A process according to claim 1 wherein a compoundof formula IV in which R′ is a tert-butoxycarbonylamino group or aformyl amino group is used.
 9. A process according to claim 1 in whichthe compounds of formula III are prepared in situ from the correspondingheteroaryl-lithium or heteroaryl-magnesium derivatives by reaction withan anhydrous zinc halide.
 10. A process according to claim 1 for thepreparation of a compound of formula II in which R₁ is a heterocyclicgroup selected between thiazolyl and thienyl.
 11. A process for thepreparation of N-mercaptoacyl derivatives of phenylalanine of formula

in which R and R₁ have the meanings reported in claim 1; R₂ is a C₂-C₄straight or branched alkyl group or an aryl or arylalkyl group havingfrom 1 to 6 carbon atoms in the alkyl moiety in which the aryl group isa phenyl or a 5 or 6 membered aromatic heterocyclic group with 1 or 2heteroatoms selected among nitrogen, oxygen and sulphur, optionallysubstituted with one or more substituents, the same or different,selected among halogen atoms, hydroxy groups, alkoxy, alkyl, alkylthio,alkylsulfonyl or alkoxycarbonyl groups having from 1 to 6 carbon atomsin the alkyl moiety, C₁-C₃ alkyl groups having one or more fluorineatoms, carboxy groups, nitro groups, amino or aminocarbonyl groups,acylamino groups, aminosulfonyl groups, mono- or di-alkylamino or mono-or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in thealkyl moiety; R₃ is a mercapto group or a R₄COS group convertible in thebody into a mercapto group in which R₄ is a C₁-C₄ straight or branchedalkyl group or a phenyl group, that comprises the reaction of a compoundof formula R₁—Zn—Y  (III) with a compound of formula

in which R, R′, X and Y have the meanings reported in claim 1; in thepresence of a transition-metal(0) based catalyst; and, when R′ is aprotected amino group, the deprotection reaction of the amino group toyield the compound of formula

in which R and R₁ have the above reported meanings.